bims-nurfca 2023-02-26 papers

Issue of 2023‒02‒26
five papers selected by
Caner Geyik
Istinye University

Biomolecules. 2023 Feb 11. pii: 353. [Epub ahead of print]13(2):

Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer?

Ruolei Wang, Lirong Liang, Misaki Matsumoto, Kazumi Iwata, Atsushi Umemura, Feng He.

The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and growth or causing cell death. Cells developed evolutionarily conserved programs to sense and adapt redox the fluctuations to regulate ROS as either signaling molecules or toxic insults. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2)-KEAP1 system is the master regulator of cellular redox and metabolic homeostasis. NRF2 has Janus-like roles in carcinogenesis and cancer development. Short-term NRF2 activation suppresses tissue injury, inflammation, and cancer initiation. However, cancer cells often exhibit constitutive NRF2 activation due to genetic mutations or oncogenic signaling, conferring advantages for cancer cells' survival and growth. Emerging evidence suggests that NRF2 hyperactivation, as an adaptive cancer phenotype under stressful tumor environments, regulates all hallmarks of cancer. In this review, we summarized the source of ROS, regulation of ROS signaling, and cellular sensors for ROS and oxygen (O2), we reviewed recent progress on the regulation of ROS generation and NRF2 signaling with a focus on the new functions of NRF2 in cancer development that reach beyond what we originally envisioned, including regulation of cancer metabolism, autophagy, macropinocytosis, unfolded protein response, proteostasis, and circadian rhythm, which, together with anti-oxidant and drug detoxification enzymes, contributes to cancer development, metastasis, and anticancer therapy resistance.

Keywords: NRF2; ROS; inflammation; metabolism; oxidative stress; unfolded protein response

DOI: https://doi.org/10.3390/biom13020353

Biomedicines. 2023 Feb 16. pii: 593. [Epub ahead of print]11(2):

NRF2 and Bip Interconnection Mediates Resistance to the Organometallic Ruthenium-Cymene Bisdemethoxycurcumin Complex Cytotoxicity in Colon Cancer Cells.

Alessia Garufi, Riccardo Pettinari, Fabio Marchetti, Mara Cirone, Gabriella D'Orazi.

Organometallic ruthenium (Ru)(II)-cymene complexes display promising pharmacological properties and might represent alternative therapeutic agents in medical applications. Polyphenols, such as curcumin and curcuminoids, display beneficial properties in medicine, including chemoprevention. Here we analyzed the anticancer effect of a cationic Ruthenium (Ru)(II)-cymene Bisdemethoxycurcumin (Ru-bdcurc) complex. The experimental data show that Ru-bdcurc induced cell death of colon cancer cells in vitro. In response to treatment, cancer cells activated the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP and NRF2, the master regulators of the unfolded protein response (UPR) and the antioxidant response, respectively. Pharmacologic targeting of either NRF2 or BiP potentiated the cytotoxic effect of Ru-bdcurc. We also found that NRF2 and UPR pathways were interconnected as the inhibition of NRF2 reduced BiP protein levels. Mechanistically, the increased Ru-bdcurc-induced cell death, following NRF2 or BiP inhibition, correlated with the upregulation of the UPR apoptotic marker CHOP and with increased H2AX phosphorylation, a marker of DNA damage. The findings reveal that BiP and NRF2 interconnection was a key regulator of colon cancer cells resistance to Ru-bdcurc cytotoxic effect. Targeting that interconnection overcame the protective mechanism and enhanced the antitumor effect of the Ru-bdcurc compound.

Keywords: BiP; CHOP; DNA damage; NRF2; cell death; chemoresistance; colon cancer; curcumin; ruthenium-cymene complex; unfolded protein response

DOI: https://doi.org/10.3390/biomedicines11020593

Cell Death Dis. 2023 Feb 23. 14(2): 151

Ibrutinib facilitates the sensitivity of colorectal cancer cells to ferroptosis through BTK/NRF2 pathway.

Jin-Feng Zhu, Yi Liu, Wen-Ting Li, Ming-Hui Li, Chao-Hui Zhen, Pei-Wei Sun, Ji-Xin Chen, Wen-Hao Wu, Wei Zeng.

Ibrutinib is a drug that inhibits the protein Burton's tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.

DOI: https://doi.org/10.1038/s41419-023-05664-9

Antioxidants (Basel). 2023 Feb 04. pii: 379. [Epub ahead of print]12(2):

Phenotypic Modulation of Cancer-Associated Antioxidant NQO1 Activity by Post-Translational Modifications and the Natural Diversity of the Human Genome.

Angel L Pey.

Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is a multifunctional and antioxidant stress protein whose expression is controlled by the Nrf2 signaling pathway. hNQO1 dysregulation is associated with cancer and neurological disorders. Recent works have shown that its activity is also modulated by different post-translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, and these may synergize with naturally-occurring and inactivating polymorphisms and mutations. Herein, I describe recent advances in the study of the effect of PTMs and genetic variations on the structure and function of hNQO1 and their relationship with disease development in different genetic backgrounds, as well as the physiological roles of these modifications. I pay particular attention to the long-range allosteric effects exerted by PTMs and natural variation on the multiple functions of hNQO1.

Keywords: acetylation; cancer; intracellular degradation; ligand-dependent stability; neurological disorders; phosphorylation; ubiquitination

DOI: https://doi.org/10.3390/antiox12020379